The project has addressed the following areas in the past year: 1. Unfolded proteins/implicit solvent models. In collaboration with Ben Schuler in Zrich, we have developed a new implicit solvent model which can capture the temperature-dependence of the solvation of unfolded proteins. This model was able to semi-quantitatively capture and provide an explanation for the observed collapse of a set of five proteins as temperature is increased. This work is described in Wuttke et al (5). It is anticipated that this model will prove useful more generally in describing the physical properties of intrinsically disordered proteins. 2. We have developed a molecular method for studying coupled folding-binding of intrinsically disordered proteins in cases where these proteins are able to bind to multiple targets. This approach has been applied to study the binding of transcription factors to co-activators, and is described in Knott & Best (3). 3. A key unresolved aspect of protein folding dynamics is the contribution of interactions within the chain to slowing folding, known as 'internal friction'. This has been detected in several recent experiments, however without a conclusive explanation. We have used molecular simulation to investigate this question, and have found that a common origin for internal friction in all proteins is crossing of local torsional barriers in the energy landscape, described in De Sancho et al (6). We are currently extending this work in an attempt to explain the variation in internal friction from protein to protein. 4. In collaboration with David de Sancho (Cambridge) and Jochen Blumberger (University College London) we have been investigating the diffusion of gas molecules to the active sites of hydrogenase enzymes. The methodology we are developing will also be generally applicable to study diffusion of any substrate molecules within enzymes, and will be combined with a description of the chemical step of binding (Ref. 4) to obtain a complete picture of the binding kinetics and mechanism.